@article{8743671,
  abstract     = {{The proto-oncogene MYB encodes the transcription factor c-MYB (cellular MYB, hereafter called MYB), which is often upregulated or aberrantly activated in cancer, including hematological malignancies.1,2 High Myb levels were especially found in acute myeloid leukemia (AML).2-4 Myb was identified initially as a retroviral oncogene (v-Myb) of avian myeloblastosis virus and E26.5,6 These retroviruses are able to transform immature hematopoietic cells in vitro and induce AMLs in chickens7 and mice.8 In leukemia patients, MYB is highly expressed, and in a subset of patients, this is a consequence of translocations, genomic duplications, or somatic mutations that involve the MYB gene itself.9-12 Furthermore, compelling evidence is accumulating that MYB also acts as a dependency factor for the maintenance of most myeloid, T-, and B-cell leukemias.13-15 Overexpression of viral MYB, a truncated form of MYB that lacks its negative regulatory domain, results in the spontaneous formation of T-cell lymphomas in mice.16 However, the in vivo roles of cellular MYB in tumor initiation remain largely unexplored. Here, we show, for the first time, that hematopoietic-specific overexpression of Myb is sufficient to drive B-cell neoplasms and myeloid malignancies in mice. To evaluate whether elevated MYB expression is sufficient to transform cells in vivo, we developed a conditional Myb overexpression (R26-Myb) mouse model (Figure 1A; supplemental Figure 1A,B) using an optimized pipeline for targeting the Rosa26 (R26) locus,17 which previously allowed us to model AML,17 mantle cell lymphoma,18 and immature T-cell leukemia19 in mice. Cre-mediated removal of the floxed stop cassette in mouse embryonic stem cells resulted in a 10-fold increase of Myb transcripts and a threefold upregulation of MYB protein (supplemental Figure 1C,D). R26Myb mice were crossed with Vav-iCre mice20 to enable R26-driven overexpression of Myb and a Firefly luciferase-reporter in the entire hematopoietic system (supplemental Figure 1E). Homozygous R26-Myb mice have a 10-to 15-fold increase in Myb RNA levels in the thymus and bone marrow (BM) (supplemental Figure 1F,G). Of note, we were not able to show increased MYB protein level of 10-week-old thymocytes (data not shown), probably because T-cell progenitors already express high endogenous MYB levels. We monitored an aging cohort of R26-Myb`g/`g; Vav-iCre`g/ 1 (hereafter named MybVav; n 5 21 with 9 males and 12 females) mice (Figure 1A) and found that 7 out of 21 (33%) animals spontaneously developed hematological malignancies (Figure 1B). Detailed necropsy was performed on 4 animals. MybVav mice had mild anemia and showed increased white blood cell and lymphocyte counts in peripheral blood (Figure 1C). In addition, 3 of them displayed splenomegaly (Figure 1D). Detailed flow cytometric analysis revealed that Myb overexpression resulted in the spontaneous development of both B-cell neoplasms and myeloid malignancies (Figure 1E,F). A selection of 1 MybVav tumor per mouse is represented in Figure 1E, while an overview of the immunophenotype of all MybVav tumors per mouse is shown in Figure 1F. A comparison of these MybVav tumors with their Cre-negative littermate controls can be found in supplemental Figure 2. Although cumulative genetic evidence suggests a role for Myb in T-cell}},
  author       = {{Pieters, Tim and Pedro Pinto De Almeida, André and T'Sas, Sara and Lemeire, Kelly and Hochepied, Tino and Berx, Geert and Kentsis, Alex and Goossens, Steven and Van Vlierberghe, Pieter}},
  issn         = {{2473-9529}},
  journal      = {{BLOOD ADVANCES}},
  keywords     = {{C-MYB,LEUKEMIA VIRUSES,EXPRESSION,ONCOGENE,ADDICTION,LOCUS,GENE}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{2987--2991}},
  title        = {{Myb drives B-cell neoplasms and myeloid malignancies in vivo}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2021005955}},
  volume       = {{6}},
  year         = {{2022}},
}

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